Inflammasome Activation Triggers Systemic Coagulation in Sepsis

脓毒症中炎症小体激活引发全身凝血

• 批准号: 10645452
• 负责人: ZHENYU Li
• 金额: $ 42.95万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10645452
• 关键词: Apoptosis; Bacteria; Bacterial Infections; Blood Coagulation Disorders; Blood Coagulation Factor; Bone Marrow; Burkholderia; CASP1 gene; Cells; Cessation of life; Clinical; Coagulation Process; Complication; Consumption; Data; Development; Disease; Disseminated Intravascular Coagulation; Escherichia coli; Family; Fibrinogen; Flagellin; Functional disorder; Goals; Gram-Negative Bacteria; In Vitro; Infection; Inflammasome; Infusion procedures; Injections; Intervention; Knockout Mice; Lead; Link; Modeling; Molecular; Morbidity - disease rate; Mus; Myelogenous; Needles; Organ; Outcome; Pathway interactions; Patients; Peripheral; Phagocytosis; Physiological; Plasma; Play; Proteins; Prothrombin time assay; Pseudomonas aeruginosa; Reagent; Research Project Grants; Rod; Role; Salmonella; Sepsis; Septic Shock; Testing; Thrombocytopenia; Thromboplastin; Thrombosis; Thrombus; Tissues; Type III Secretion System Pathway; Work; antithrombin III-protease complex; base; cecal ligation puncture; driving force; in vivo; insight; intravenous injection; macrophage; monocyte; mortality; mouse model; multidisciplinary; new therapeutic target; protein E; release factor; septic patients; targeted treatment

Abstract Septic shock is invariably associated with systemic coagulation leading to thrombus formation. Sepsis-related organ dysfunction has been attributed to microvascular thrombosis. Mortality rate doubles in septic patients with disseminated intravascular coagulation (DIC). DIC is even considered as a sign that “death is coming”. Previous studies have demonstrated the important roles of tissue factor (TF) in sepsis-associated DIC. However, the mechanism leading to TF release, which triggers systemic coagulation in sepsis, is unknown. Recent in vitro studies revealed that bacterial components (flagellin, the rod protein of the type III secretion system (T3SS), or LPS) induce programmed cell death (called pyroptosis) of macrophages through activation of inflammasome pathways. We show that intravenous injection of a T3SS rod protein E. coli, EprJ, induced depletion of peripheral monocytes and macrophages in tissues. Importantly, injection of EprJ or LPS, which elicit canonical and noncanonical inflammasome activation, respectively, induced systemic coagulation activation, as evident by prolonged prothrombin time (PT) due to increased consumption of coagulation factors, thrombocytopenia, increased plasma levels of thrombin-antithrombin complex (TAT), and reduced plasma fibrinogen levels. Thus, our findings made connections between the in vitro and in vivo observations and suggested monocyte/macrophage pyroptosis as a trigger of DIC in sepsis. The goal of this application is to delineate the underlying mechanisms by which inflammasome activation and pyroptosis trigger DIC in sepsis. Specific Aim 1 will establish inflammasome activation and pyroptosis as a common mechanism for DIC induced by bacterial infection. The working hypothesis is that bacteria and bacterial components from different strains elicit DIC through Inflammasome activation and pyroptosis. We will use a combination of various deficient mice to elucidate the role of inflammasome activation and pyroptosis in DIC elicited by Gram-negative bacteria. Specific Aim 2 is to identify the molecular mechanism of TF release from macrophages following inflammasome activation. We will also use the myeloid-specific TF knockout mice and a low TF mouse model to elucidate whether DIC elicited by the bacterial components depends on release of TF from macrophages. Specific Aim 3 will demonstrate the role of inflammasome activation in sepsis-associated coagulopathy. We will use the cecal ligation and puncture (CLP) sepsis model and bacterial infusion sepsis model to investigate the role of inflammasome activation and pyroptosis in coagulation. Completion of the proposed studies will demonstrate the molecular mechanism of systemic coagulation is sepsis. Such findings would have profound ramifications for the identification of new drug targets for DIC, the deadly complication of sepsis.

抽象的 败血性休克总是与全身性凝血相关，从而导致血栓形成。败血症有关 器官功能障碍归因于微血管血栓形成。化脓性患者的死亡率增加一倍 散布血管内凝血（DIC）。 DIC甚至被认为是“死亡即将来临”的标志。 先前的研究表明，组织因子（TF）在与败血症相关的DIC中的重要作用。 然而，导致TF释放的机制触发了败血症的全身性凝血。 最近的体外研究表明，细菌成分（鞭毛蛋白，III型分泌的棒蛋白 系统（T3SS）或LPS）通过激活诱导巨噬细胞的程序性细胞死亡（称为pyproptosis） 炎性途径。我们表明，静脉注射T3SS杆蛋白大肠杆菌EPRJ诱导 组织中周围单核细胞和巨噬细胞的耗竭。重要的是，注射EPRJ或LPS， 分别引起规范和非规范炎症体激活，引起全身凝结 由于凝血因子的消耗增加，激活是由长时间的凝血酶原时间（PT）所证明的， 血小板减少症，凝血酶 - 抗凝结蛋白复合物（TAT）的血浆水平升高，血浆降低 纤维蛋白原水平。这，我们的发现在体外和体内观察结果之间建立了联系 建议的单核细胞/巨噬细胞凋亡是败血症中DIC的触发。该应用的目的是 描述炎症体激活和凋亡触发败血症的基本机制。 特定的目标1将建立炎症体激活和凋亡作为DIC的常见机制 由细菌感染诱导。有效的假设是来自不同的细菌和细菌成分 菌株通过炎症体激活和凋亡引起DIC。我们将结合各种 缺乏小鼠以阐明司法阴性在DIC中的炎症体激活和革兰氏阴性症的作用 细菌。具体目标2是确定从巨噬细胞中释放TF的分子机制 炎症体激活。我们还将使用髓样特异性TF敲除小鼠和低TF鼠标模型 为了阐明细菌成分引起的DIC是否取决于从巨噬细胞中释放TF。 具体的目标3将证明炎性体激活在与败血症相关的凝血病中的作用。我们将 使用盲肠结扎和穿刺（CLP）败血症模型和细菌输注败血症模型来研究 炎性体激活和凋亡在凝结中的作用。拟议研究的完成将 证明全身凝结的分子机制是败血症。这样的发现将有深远的 鉴定新药靶标的DIC的后果，败血症的致命并发症。

项目成果

Inhibiting NINJ1-dependent plasma membrane rupture protects against inflammasome-induced blood coagulation and inflammation.

抑制 NINJ1 依赖性质膜破裂可防止炎症体诱导的凝血和炎症。

• DOI: 10.1101/2023.08.30.555561
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Cui,Jian;Li,Hua;Zhang,Guoying;Zhang,Yan;Yang,Ling;Sim,MarthaMS;Wood,JeremyP;Wei,Yinan;Li,Zhenyu;Wu,Congqing
• 通讯作者: Wu,Congqing

Inflammasome activation and pyroptosis mediate coagulopathy and inflammation in Salmonella systemic infection.

• DOI: 10.1016/j.micres.2023.127460
• 发表时间: 2023-10
• 期刊: MICROBIOLOGICAL RESEARCH
• 影响因子: 6.7
• 作者: Pandeya, Ankit;Zhang, Yan;Cui, Jian;Yang, Ling;Li, Jeffery;Zhang, Guoying;Wu, Congqing;Li, Zhenyu;Wei, Yinan
• 通讯作者: Wei, Yinan

Calcium Ion Chelation Preserves Platelet Function During Cold Storage.

• DOI: 10.1161/atvbaha.120.314879
• 发表时间: 2021-01
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Xiang B;Zhang G;Zhang Y;Wu C;Joshi S;Morris AJ;Ware J;Smyth SS;Whiteheart SW;Li Z
• 通讯作者: Li Z